How are health technology assessment bodies responding to the assessment challenges posed by cell and gene therapy?

BACKGROUND: The aims of this research were to provide a better understanding of the specific evidence needs for assessment of clinical and cost-effectiveness of cell and gene therapies, and to explore the extent that the relevant categories of evidence are considered in health technology assessment (HTA) processes. METHODS: A targeted literature review was conducted to identify the specific categories of evidence relevant to the assessment of these therapies. Forty-six HTA reports for 9 products in 10 cell and gene therapy indications across 8 jurisdictions were analysed to determine the extent to which various items of evidence were considered. RESULTS: The items to which the HTA bodies reacted positively were: treatment was for a rare disease or serious condition, lack of alternative therapies, evidence indicating substantial health gains, and when alternative payment models could be agreed. The items to which they reacted negatively were: use of unvalidated surrogate endpoints, single arm trials without an adequately matched alternative therapy, inadequate reporting of adverse consequences and risks, short length of follow-up in clinical trials, extrapolating to long-term outcomes, and uncertainty around the economic estimates. CONCLUSIONS: The consideration by HTA bodies of evidence relating to the particular features of cell and gene therapies is variable. Several suggestions are made for addressing the assessment challenges posed by these therapies. Jurisdictions conducting HTAs of these therapies can consider whether these suggestions could be incorporated within their existing approach through strengthening deliberative decision-making or performing additional analyses.

The Role of Indication-Based Pricing in Future Pricing and Reimbursement Policies: A Systematic Review.

OBJECTIVES: Indication-based pricing (IBP) has received growing attention because of the expected increase in the number of new medicines with multiple indications. In our systematic review, we assess the potential benefits, barriers, current experiences, and future perspectives of different IBP mechanisms. METHODS: We searched publications in English, Spanish, or French assessing the impact, international experience, and future context of IBP systems on PubMed, Scopus, Cochrane, EconLit, American Society of Clinical Oncology, and National Institute for Health Research Health Technology Assessment from 2000 to 2020. This was complemented by a gray literature search in Google Scholar. RESULTS: A total of 29 publications that specifically addressed the topic of IBP were retained. The most commonly reported benefits of IBP were a better alignment of medicines' value and price, optimization of research and development incentives and increase of competition, and improvement of patients' access to treatments. Data collection and proper infrastructures, and the risk of high administrative burden and associated costs, were seen as the main barriers for proper IBP implementation. International experience lacks concrete examples of IBP. A single weighted average price according to volume, value, or a combination of both, appears to be the most used methodology, followed by different confidential net prices per indication. Different brands with distinct price per indication are less common, although it is considered a pure IBP system. CONCLUSIONS: Evidence of IBP impact is still scarce, and there is a need for pilot projects and experiences to monitor its real consequences. An appropriate price and reimbursement model for multi-indication medicines should be a priority, but political will and proper data collection systems remain crucial.

Description of day case costs and tariffs of cataract surgery from a sample of nine European countries.

BACKGROUND: The lack of transparency in the methodology of unit cost estimation and the usage of confidential or undisclosed information prevents cost comparisons and makes the transferability of the results across countries difficult. The objective of this article is to compare the methodologies used in the estimation of the cost of a day case cataract extirpation that are described in the official and publicly available sources and to study how these translate into different unit cost estimates. METHODS: A literature review was conducted to identify the main sources of unit costs of cataract extirpation. A semi-structured questionnaire to obtain information on national costing methodologies was developed and sent to consortium partners in nine European countries. Additionally, publicly available sources of unit cost of cataract surgery in those countries included in the European Healthcare and Social Cost Database (EU HCSCD) were analysed. RESULTS: The findings showed a considerable diversity across countries on unit costs varying from 432.5€ in Poland (minor degree of severity) to 3411.96€ in Portugal (major degree of severity). In addition, differences were found in the year of cost publication and on the level of detail of different types of cataract surgery. The unit of activity were Diagnosis-Related Groups in all countries except Slovenia. All unit costs include direct costs and variable overheads (except Germany where nursing costs are financed separately). Differences were identified in the type of fixed overheads included in unit costs. Methodological documents explaining the identification, measurement and evaluation of resources included in the unit costs, as well as use of appropriate cost drivers are publicly available only in England, Portugal and Sweden. CONCLUSIONS: We can conclude that while unit costs of cataract extirpation are publicly available, the information on methodological aspects is scarce. This appears to pose a significant problem for cross-country comparisons of costs and transferability of results from one country to another.

Development of the European Healthcare and Social Cost Database (EU HCSCD) for use in economic evaluation of healthcare programs.

INTRODUCTION: Costs are one of the critical factors for the transferability of the results in health technology assessment and economic evaluation. The objective is to develop a cost database at the European level to facilitate cross-border cost comparisons in different settings and explains the factors that lead to differences in healthcare costs in different countries, taking into account the differences between health systems and other factors. METHODOLOGY: The core of the database is compounded of three main categories (primary resources, composite goods and services, and complex processes and interventions) organized into 13 subcategories. A number of elements providing as detailed information of unit cost as possible were identified in order to mitigate the problem of comparability. Consortium partners validated both the database structure and selected costing items. RESULTS: Twenty-seven costing items included in the EU HCSCD resulted in 1450 unit costs when taking into account all item subtypes and countries. Cross-country differences in costs are driven by the type of resources included in the costing items (e.g., overhead costs in case of complex processes and interventions) or by the variety of existing brands and/or models and the type of unit value in most of the primary resources. CONCLUSION: The EU HCSCD is the only public unit healthcare and social cost database at European level that gather data on unit costs and explains differences in costs across countries. Its maintenance and regular data updating will enable establishing specific systems for generating and recording information that will meet many of its current limitations.

A multi-criteria decision analysis on the value of nintedanib for interstitial lung diseases.

OBJECTIVES: Our aim was to assess the value of nintedanib for non-idiopathic progressive fibrosing interstitial lung disease (non-IPF PF-ILD) and systemic sclerosis-associated ILD (SSc-ILD) in the Spanish context, using a multi-criteria decision analysis (MCDA). METHODS: Following an adaptation of the Evidence and Value: Impact on DEcision Making (EVIDEM) MCDA methodology, the estimated value of nintedanib was obtained by means of an additive linear model that combined individual weights (100-points distribution) of criteria with the individual scoring of nintedanib in each criterion for every indication, assigned by a multidisciplinary committee of twelve clinicians, patients, pharmacists, and decision-makers. To assess the reproducibility, an alternative weighting method was applied, as well as a re-test of weights and scores at a different moment of time. RESULTS: The experts committee recognized nintedanib as an intervention with a positive value contribution in comparison to placebo for the treatment of non-IPF PF-ILD (0.50 ± 0.16, on a scale from -1 to 1) and SSc-ILD (0.40 ± 0.12), diseases which were considered as very severe and with high unmet needs. The drug was perceived as a treatment that provides an added therapeutic benefit for patients (0.06-0.07), given its proven clinical efficacy (0.05-0.06), slight improvements in patient-reported outcomes (0.01-0.02), and similar safety profile than placebo (-0.04-0.00), which will likely be positioned as a recommended therapy in the next clinical practice guidelines updates. CONCLUSIONS: Under this increasingly used methodology, nintedanib has shown to provide a positive value estimate for non-IPF PF-ILD and SSc-ILD when compared to placebo in Spain.

Cost transferability problems in economic evaluation as a framework for an European health care and social costs database.

This article presents part of the work within Work Package 3 (WP3) of Impact HTA (Improved methods and actionable tools for enhancing HTA), a H2020 EU-funded research project, intended to enhance and promote collaboration in HTA across EU MS. Amongst other objectives, and in close collaboration with WP4, WP3 addressed setting up a multi-country unit-cost database: the European health care and social costs database (EU HCSCD). The purpose of the database is to facilitate the transference of healthcare economic evaluation analyses across countries, jurisdictions and settings. WP3 concentrates on healthcare costs; WP4 on social costs. This paper discusses the state of the art on this topic, building an appropriate conceptual and theoretical framework for Database development. We conducted a broad, but not systematic, literature and gray-literature review (LR), identifying existing practices and problems, and their implications, described in the Results section. We discuss practical implications and draw important conclusions behind the construction, and future evolution, of this database.

Development of a core evaluation framework of value-added medicines: report 2 on pharmaceutical policy perspectives.

BACKGROUND: A core evaluation framework that captures the health care and societal benefits of value added medicines (VAMs, also often called repurposed medicines) was proposed in Report 1, aiming to reduce the heterogeneity in value assessment processes across countries and to create incentives for manufacturers to invest into incremental innovation. However, this can be impactful only if the framework can be adapted to heterogeneous health care financing systems in different jurisdictions, and the cost of evidence generation necessitated by the framework takes into account the anticipated benefits for the health care system and rewards for the developers. AREAS COVERED: The framework could potentially improve the pricing and reimbursement decisions of VAMs by adapting it to different country specific decision-contexts such as deliberative processes, augmented cost-effectiveness frameworks or formal multi-criteria decision analysis (MCDA); alternatively, some of its domains may be added to current general evaluation frameworks of medicines. The proposed evaluation framework may provide a starting point for practices based on which VAMs can be exempted from generic pricing mechanisms or can be integrated into the reimbursement and procurement system, allowing for price differentiation according to their added value. Besides evidence from RCTs, pricing and reimbursement decision processes of VAMs should allow for ex-ante non-RCT evidence for certain domains. Alternatively, relying on ex-post evidence agreements-such as outcome guarantee or coverage with evidence development-can also reduce decision uncertainty. CONCLUSIONS: The core evaluation framework for VAMs could trigger changes in the existing pricing, reimbursement and procurement practices by improving the appraisal of the added value created by incremental innovation.

Development of a core evaluation framework of value-added medicines: report 1 on methodology and findings.

BACKGROUND: Medicines that are based on known molecules and are further developed to address healthcare needs and deliver relevant improvement for patients, healthcare professionals and/or payers are called value-added medicines (VAMs). The evaluation process of VAMs is heterogeneous across countries, and it has been primarily designed for originator pharmaceuticals with confirmatory evidence collected alongside pivotal clinical trials. There is a mismatch between evidence requirements by public decision-makers and evidence generated by manufacturers of VAMs. Our objective was to develop a core evaluation framework for VAMs. METHODS: Potential benefits offered by VAMs were collected through a systematic literature review and allocated to separate domains in an iterative process. The draft list of domains and their applicability were validated during two consecutive virtual workshops by health policy experts representing countries with different economic statuses, geographical and decision-making contexts. RESULTS: Based on 158 extracted studies, the final consensus on the evaluation framework resulted in 11 value domains in 5 main clusters, including unmet medical needs, health gain (measured by health care professionals), patient-reported outcomes, burden on households, and burden on the health care system. CONCLUSIONS: The proposed framework could reduce the heterogeneity in value assessment processes across countries and create incentives for manufacturers to invest in incremental innovation. However, some domains may not be equally relevant or accepted in all countries, therefore the core framework needs thorough adaptation in specific jurisdictions.

PRIORITIES FOR HEALTH ECONOMIC METHODOLOGICAL RESEARCH: RESULTS OF AN EXPERT CONSULTATION.

BACKGROUND: The importance of economic evaluation in decision making is growing with increasing budgetary pressures on health systems. Diverse economic evidence is available for a range of interventions across national contexts within Europe, but little attention has been given to identifying evidence gaps that, if filled, could contribute to more efficient allocation of resources. One objective of the Research Agenda for Health Economic Evaluation project is to determine the most important methodological evidence gaps for the ten highest burden conditions in the European Union (EU), and to suggest ways of filling these gaps. METHODS: The highest burden conditions in the EU by Disability Adjusted Life Years were determined using the Global Burden of Disease study. Clinical interventions were identified for each condition based on published guidelines, and economic evaluations indexed in MEDLINE were mapped to each intervention. A panel of public health and health economics experts discussed the evidence during a workshop and identified evidence gaps. RESULTS: The literature analysis contributed to identifying cross-cutting methodological and technical issues, which were considered by the expert panel to derive methodological research priorities. CONCLUSIONS: The panel suggests a research agenda for health economics which incorporates the use of real-world evidence in the assessment of new and existing interventions; increased understanding of cost-effectiveness according to patient characteristics beyond the "-omics" approach to inform both investment and disinvestment decisions; methods for assessment of complex interventions; improved cross-talk between economic evaluations from health and other sectors; early health technology assessment; and standardized, transferable approaches to economic modeling.

Dietary supplements in child and adolescent psychiatry.

Complementary and alternative treatments, including dietary supplements, are very popular and increasingly used in developed countries. Some features such as accessibility, ease of use, the possibility of self-administration and the belief they are safe without side effects, have led to an increase in their consumption. However, there is limited evidence of the effectiveness and safety of these treatments because of methodological issues. The level of scientific evidence is particularly low and weak in the field of child and adolescent Psychiatry. The purpose of this article is to give an updated overview of dietary treatments in this area. We make a brief introduction about general questions, including legal aspects, and propose general practical recommendations for a proper management by the families that choose these treatments. We focus on reviewing the current state of research into dietary treatments in some childhood and juvenile psychiatric disorders, highlighting current evidence of specific treatments. The final purpose of this article is to describe the level of current evidence on dietary treatments and to provide professionals involved in the care of children and adolescents with a useful tool to help, guide and educate families about their use in order to achieve the greatest benefit to patients.

Risk of second cancers cancer after a first primary breast cancer: a systematic review and meta-analysis.

OBJECTIVE: To examine the scientific evidence and the risk of second primary cancers in women diagnosed with a first primary breast cancer. METHODS: The literature was searched in Pubmed and Embase and included studies published up to June 2013, using population-based data and IARC/AICR codification rules for multiple primary cancers. A qualitative synthesis was carried out and the methodological quality of the studies evaluated. Standardised incidence ratios (SIRs) on second cancer risk, weighted by the standard error of each study, were pooled using fixed and random effects models. SIRs were also pooled by age at diagnosis (<50 and ≥ 50 years), and time since diagnosis of the first breast cancer (<10 and ≥ 10 years). RESULTS: 15 out of 710 articles fulfilled the inclusion criteria. All of them were retrospective cohort studies either population-based (13 studies) or hospital-based studies (2 studies). The studies varied with respect to number of cases, selection criteria, definition of multiple primary cancers, and the second cancer sites included. SIRs reported in these studies for all cancers combined varied from 1.0 to 1.4. The pooled SIR estimate for second cancer risk was 1.17 (95% CI: 1.10-1.25). By age groups, SIR estimates were 1.51 (95% CI: 1.35-1.70) for women younger than 50 years and 1.11 (95% CI: 1.02-1.21) for those who were older. Women with breast cancer are at risk of second cancers within the first 10 years after the first breast cancer diagnosis (SIR: 1.19; 95% CI: 1.06-1.33), and thereafter (SIR: 1.26; 95% CI: 1.05-1.52). CONCLUSION: This higher risk of second cancers in women diagnosed with a first primary breast cancer with respect to the general population emphasises the importance of prevention and control policies aimed at reducing incidence of second cancers.

Tiered Pricing and Alternative Mechanisms for Equitative Access to Vaccines in Latin America: A Narrative Review of the Literature.

OBJECTIVES: To review and describe alternative strategies for the supply of vaccines in Latin America. METHODS: We conducted a narrative review to explore and describe alternatives for equitable vaccine access in Latin America. We searched and considered the main access strategies reported in the literature through PubMed, Science Direct, and Google Scholar. Additionally, we reviewed the web sites of key stakeholders. The search was conducted using the following keywords: ("access" or "availability" or "acquisition" or "affordability" or "tiered pricing") and ("vaccine"). Subsequently, documents that met the inclusion criteria were selected. Finally, findings were grouped by means of a thematic analysis and an interpretative synthesis. RESULTS: Twenty-four publications were included. We identified 5 main topics: current supply strategies, challenges for the acquisition of vaccines, vaccine prices equity, alternative supply strategies, and the advantages and impact of a tiered pricing strategy. CONCLUSIONS: Our review suggests that tiered pricing can be an tool for accelerating the process of introducing vaccines in low-income countries at affordable prices and for countries that do not adhere to the current procurement mechanisms or are not eligible for Vaccine Alliance because giving countries prices for vaccines that reflect their ability to pay can result in better programmatic and financial planning for the purchase of these vaccines, and in return, vaccine manufacturers can gain access to wider markets However, this model has not been z improve access to vaccines that are aimed only at developing countries, mainly because the market in these countries is not profitable for producers.

The Efficiency of Increased HCV Testing and Treatment Strategies in Spain to Achieve Elimination Goals.

BACKGROUND: In 2015, Spain launched a national eradication strategy for hepatitis C virus (HCV), resulting in the highest treatment rate in Europe and substantial reductions in HCV prevalence. However, to achieve the goal of HCV elimination, it is necessary to scale-up the diagnosis, treatment, and management of HCV infection. OBJECTIVE: Our aim was to assess the prevalence, incidence, and cost effectiveness of scaling-up compared with status quo scenarios. METHODS: A compartmental dynamic transmission model was developed comprising of a cascade of care and a liver progression module. Cost and quality-of-life inputs were sourced from the literature. Key outcomes were the prevalence and incidence of HCV and the incremental cost per quality-adjusted life-year (QALY) and per life-year (LY). Outcomes for a hypothetical elimination strategy were compared with the status quo. RESULTS: The base-case analysis found that scaling-up testing and treatment reduced both the prevalence and incidence of HCV over time, resulting in incremental costs per QALY and LY of €13,291 and €12,285 respectively, compared with the status quo. The main drivers of the cost-effectiveness results included cost of diagnosis, cost of treatment, proportion of people who are unaware, percentage of population who inject drugs, and calibration parameters related to HCV infection prevalence. CONCLUSIONS: This analysis demonstrated that scaling-up testing and treatment with direct-acting antivirals may be an efficient strategy for reducing the incidence and prevalence of HCV and may help achieve HCV elimination goals in Spain.

Convined clinical prognostic model in colorectal cancer.

Current staging systems in patients with colorectal cancer (CRC) utilize relatively few patient characteristics in comparison to the breadth of information available. The objective of our study is to analyze the heterogeneous set of variables that may influence mortality and recurrence independently in patients with CCR, and prepare a predictive model of survival and recurrence. Data from 288 patients who had undergone scheduled surgery for stage I-III cancer of the colon and upper rectum were used to construct Cox models for DFS and overall CSS at five years. We have jointly examined clinical variables, serological markers and histological variables with the aim of identifying new prognostic factors. Internal and external validation was carried out on each of the nomograms obtained. Perineural invasion; high platelet-lymphocyte ratio (PLR) and the pN stage were the variables that emerged as an independent risk factor of recurrence. The variables related independently to overall CSS were the presence of blood in stools, high PLR and nodal involvement. We have created a predictive model of recurrence and mortality at 5 years with data that is easily available (clinical, analytical and histological variables) which can help personalize the treatment and follow-up of patients with CRC. We also conducted an adequate internal and external validation.

Innovations in pharmaceutical policies and learnings for sustainable access to affordable medicines.

Sustainable access to affordable medicines remains a public health issue globally, including for high-income countries. To foster the debate on avenues for the future, the fifth PPRI Conference held in Vienna on 25 and 26 April 2024 will offer a forum for the debate on innovating pharmaceutical policymaking to develop and implement futureproof policy options, which are able to address current and future challenges. The Conference invites a broad audience of stakeholders, including researchers, policymakers, payers, patients, industry and health professionals. The conference topics are organised in three strands: Strand 1 on 'Local challenges, global learnings' aims to contribute to lively discussions on the implementation of pharmaceutical policies across the globe. Best-practice examples will be presented, supplemented by case studies of less effective policies which can offer rich learnings. Strand 2 on 'Strengthening the evidence base' is the place for presentations and discussions on topics such as health technology assessments, managed entry agreements and real-world data. Strand 3 'Futureproofing pharmaceutical policies' is particularly dedicated to explore innovation in policymaking to achieve sustainable access to affordable medicines.

Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries.

Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022. Methods: A survey was distributed in July 2022 to representatives of 46 countries. Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs. Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe's Access to Novel Medicines Platform.

Clinical Outcomes of First-line Therapies for Advanced Non-Small Cell Lung Cancer: A Systematic Review of Trials Published Between 2010 and 2020.

OBJECTIVES: To analyze the evolution of clinical outcomes derived from clinical trials on first-line therapies for advanced or metastatic non-small cell lung cancer (NSCLC) published between 2010 and 2020, focusing on how these outcomes impact survival rates and management of patients. METHODS: A systematic review of phase III and pivotal phase II clinical trials was conducted by a structured search on Medline and Embase. A comprehensive set of variables was collected to assess their influence on survival rates. We also estimated the clinical benefit by applying the ESMO-MCBS v1.1 and extracted the authors' conclusions. RESULTS: Sixty-six studies involving 34,951 patients were included. Best survival outcomes were found for nonsquamous non-small cell lung cancer (OS and progression-free survival medians: 19.4 and 10.2 mo) and for those expressing molecular targets (OS and progression-free survival medians: 23.8 and 11.0 mo). No significant influence on survival rates was observed for industry funding and disease stage (IIIB/IV vs. IV). ESMO-MCBS v1.1 was applied in 45 positive studies and resulted in a meaningful clinical benefit score in 37.8%. Quality of life (QoL) was reported in 57.6% of the original publications and showed statistical significance favoring the experimental arm in 33.3%. Positive authors' conclusions (75.7% of trials) were based on OS and/or QoL in 34% and on surrogate endpoints in 66%. CONCLUSIONS: Extended survival times and a steady improvement in QoL have been observed. However, there were more than twice as many studies reporting positive authors' conclusions as studies meeting the ESMO threshold for meaningful clinical benefit.

Review and Assessment of Policy Options for Improving Access to Combination Therapies in Oncology in Europe.

OBJECTIVES: Combinations of on-patent therapies (CTs) are increasingly common in oncology. They cause challenges for funding and affordability, and hence patient access, especially when constituent therapies are owned by different manufacturers. The aim of our study was to develop policy proposals for the assessment, pricing, and funding of CTs and identify which might be relevant in different European countries. METHODS: Following a review of available literature, seven hypothetical policy proposals were developed and subsequently assessed through 19 semi-structured interviews with health policy, pricing, technology assessment and legal experts in seven European countries to identify those most likely to gain traction. RESULTS: Experts saw a need for agreed approaches within a country to manage affordability and funding challenges for CTs. Changes to health technology assessment (HTA) and funding models were considered unlikely, but other policy proposals were seen as mostly useful, with country-specific adaptations. Bilateral discussions between manufacturers and payers were deemed important, and less challenging and protracted than arbitrated dialogue between manufacturers. Usage-specific pricing, possibly using weighted average prices, was considered a prerequisite for the financial management of CTs. CONCLUSIONS: There is a growing need to ensure that CTs are affordable to health systems. It would appear that there is no one set of policies that is appropriate for all countries in Europe, so countries wishing to ensure that patients have (or continue to have) access to CTs of value to them must explore and implement the policies that are best suited to their general approach to funding health care and to the assessment and reimbursement of medicines.

The cost-effectiveness of a uniform versus age-based threshold for one-off screening for prevention of cardiovascular disease.

The objective of this article was to assess the cost-effectiveness of screening strategies for cardiovascular diseases (CVD). A decision analytic model was constructed to estimate the costs and benefits of one-off screening strategies differentiated by screening age, sex and the threshold for initiating statin therapy ("uniform" or "age-adjusted") from the Spanish NHS perspective. The age-adjusted thresholds were configured so that the same number of people at high risk would be treated as under the uniform threshold. Health benefit was measured in quality-adjusted life years (QALY). Transition rates were estimated from the European Prospective Investigation into Cancer and Nutrition (EPIC-CVD), a large multicentre nested case-cohort study with 12 years of follow-up. Unit costs of primary care, hospitalizations and CVD care were taken from the Spanish health system. Univariate and probabilistic sensitivity analyses were employed. The comparator was no systematic screening program. The base case model showed that the most efficient one-off strategy is to screen both men and women at 40 years old using a uniform risk threshold for initiating statin treatment (Incremental Cost-Effectiveness Ratio of €3,274/QALY and €6,085/QALY for men and women, respectively). Re-allocating statin treatment towards younger individuals at high risk for their age and sex would not offset the benefit obtained using those same resources to treat older individuals. Results are sensitive to assumptions about CVD incidence rates. To conclude, one-off screening for CVD using a uniform risk threshold appears cost-effective compared with no systematic screening. These results should be evaluated in clinical studies.

Secretion of Interleukin 6 in Human Skeletal Muscle Cultures Depends on Ca2+ Signalling.

The systemic effects of physical activity are mediated by the release of IL-6 and other myokines from contracting muscle. Although the release of IL-6 from muscle has been extensively studied, the information on the cellular mechanisms is fragmentary and scarce, especially regarding the role of Ca2+ signals. The aim of this study was to characterize the role of the main components of Ca2+ signals in human skeletal muscle cells during IL-6 secretion stimulated by the Ca2+ mobilizing agonist ATP. Primary cultures were prepared from surgical samples, fluorescence microscopy was used to evaluate the Ca2+ signals and the stimulated release of IL-6 into the medium was determined using ELISA. Intracellular calcium chelator Bapta, low extracellular calcium and the Ca2+ channels blocker La3+ reduced the ATP-stimulated, but not the basal secretion. Secretion was inhibited by blockers of L-type (nifedipine, verapamil), T-type (NNC55-0396) and Orai1 (Synta66) Ca2+ channels and by silencing Orai1 expression. The same effect was achieved with inhibitors of ryanodine receptors (ryanodine, dantrolene) and IP3 receptors (xestospongin C, 2-APB, caffeine). Inhibitors of calmodulin (calmidazolium) and calcineurin (FK506) also decreased secretion. IL-6 transcription in response to ATP was not affected by Bapta or by the T channel blocker. Our results prove that ATP-stimulated IL-6 secretion is mediated at the post-transcriptional level by Ca2+ signals, including the mobilization of calcium stores, the activation of store-operated Ca2+ entry, and the subsequent activation of voltage-operated Ca2+ channels and calmodulin/calcineurin pathways.